Controlled release of artemisone for the treatment of experimental cerebral malaria

Abstract

Background: Cerebral malaria (CM) is a leading cause of malarial mortality resulting from infection by Plasmodium falciparum. Treatment commonly involves adjunctive care and injections or transfusion of artemisinins. All artemisinins that are in current use are metabolized to dihydroxyartemisinin (DHA), to which there is already some parasite resistance. We used artemisone, a derivative that does not convert to DHA, has improved pharmacokinetics and anti-plasmodial activity and is also anti-inflammatory (an advantage given the immunopathological nature of CM). Methods: We examined controlled artemisone release from biodegradable polymers in a mouse CM model. This would improve treatment by exposing the parasites for a longer period to a non-toxic drug concentration, high enough to eliminate the pathogen and prevent CM. The preparations were inserted into mice as prophylaxis, early or late treatment in the disease course. Results: The most efficient formulation was a rigid polymer, containing 80 mg/kg artemisone, which cured all of the mice when used as early treatment and 60% of the mice when used as a very late treatment (at which stage all control mice would die of CM within 24 h). In those mice that were not completely cured, relapse followed a latent period of more than seven days. Prophylactic treatment four days prior to the infection prevented CM. We also measured the amount of artemisone released from the rigid polymers using a bioassay with cultured P. falciparum. Significant amounts of artemisone were released throughout at least ten days, in line with the in vivo prophylactic results. Conclusions: Overall, we demonstrate, as a proof-of-concept, a controlled-sustained release system of artemisone for treatment of CM. Mice were cured or if treated at a very late stage of the disease, depicted a delay of a week before death. This delay would enable a considerable time window for exact diagnosis and appropriate additional treatment. Identical methods could be used for other parasites that are sensitive to artemisinins (e.g. Toxoplasma gondii and Neospora caninum).